1. Field of the Invention
This invention relates to novel compositions useful in the treatment of metabolically impaired patients and in promoting enhanced patient compliance. Within the scope of the invention are non-racemic mixtures of certain chiral spirofluorenehydantoins, which may be used to prevent glucose toxicity arising from the intracellular reduction of glucose to sorbitol. More specifically, the compositions of this invention may be used in the treatment of sequelae of neuropathy, cataract vasculopathies, retinopathy and other complications arising from diabetes mellitus. The invention also relates to methods of treatment using such compositions.
2. Description of Related Art
Subsequent to administration, many commonly prescribed drugs undergo metabolic oxidation brought about by various oxidative agents normally produced by the body. Some patients, however, because of their genetic make-up, may fail to produce sufficient amounts of the necessary metabolizing agent(s). Others may have a frank deficiency or dysfunction of drug metabolizing tissue due to hepatitis, alcoholism or other chronic disease. In either case, such patients will be referred to as "metabolically impaired" or a "poor drug metabolizer." Patients with substantially normal metabolic capabilities are referred to as "extensive metabolizers."
Certain chronic disease patients, such as diabetes mellitus patients, can be at significant risk during drug therapy if they are poor drug metabolizers. They exhibit impaired drug metabolism because of genetic predisposition, liver/kidney disease, obesity, advanced age, or a combination of two or more of these factors. Liver and kidney damage, respectively, may occur as a result of cirrhosis associated with chronic pancreatitis and chronic hyperglycemia in the diabetic patient. However, liver cirrhosis might also arise due to alcoholism, hepatitis, etc., which are not diabetic sequelae. It follows that an alcoholic or diabetic patient with advanced kidney and liver disease, who is also genetically a poor drug metabolizer, is at extreme risk of drug toxicity.
Even an otherwise healthy diabetic patient can be a poor drug metabolizer when that subject cannot genetically express a particular drug metabolizing enzyme. This defect can have clinical significance when it slows drug intermediary metabolism, detoxification and disposition. This slowing can cause drug accumulation and a toxicity which resembles a drug overdose. In addition, this drug accumulation can cause the production of abnormal intermediary metabolites which can result in other insidious toxic side-effects. In summary, certain drugs with narrow therapeutic indices can become acutely toxic, even fatal, while others may cause longer term side-effects.
Nevertheless, a drug at a fixed dose has historically been used to serve the therapeutic needs of a broad spectrum of patients without regard to their metabolic status. Consequently, patients with metabolic limitations have occasionally suffered adverse reactions due to toxic drug accumulation. An understanding of the particular patient's drug metabolizing ability will facilitate more appropriate prescribing. Increasingly it is possible to predict the drug metabolizing ability of a patient and this will in certain instances permit selection of a safe drug dosage for that individual. However, a short-acting drug which might be selected for the safety of poor metabolizers will ordinarily require daily multi-dosing in the extensive metabolizer to provide equivalent therapeutic benefit. In chronic disease therapy, these multi-dose per day drugs often fail because of patient noncompliance to self-medicare. Consequently, because most patients are extensive metabolizers, there is a bias favoring relatively longer acting drugs, which may not be well tolerated by poor metabolizers.
With respect to diabetes mellitus, racemic mixtures and the R and S enantiomers of certain chiral spirofiuorenehydantoins have previously been reported to be aldose reductase inhibitors and thus of value in controlling complications arising from that disease (e.g., diabetic cataracts and neuropathy). Reference is made to commonly assigned U.S. Pat. No. 4,864,028 (York) for further background in this regard. The entire contents U.S. Pat. No. 4,864,028 relating to the utility, structure and synthesis of such chiral spirofluorenehydantoins are hereby incorporated in the present specification by reference.
Examples of enantiomers of a given compound having different degrees of pharmacokinetic or pharmacodynamic properties are known to those skilled in the art. See, e.g., Drayer, D. E., Clin. Pharmacol. Ther. 40:125-133 (1986). In the case of aldose reductase inhibitors, certain enantiomers have been described as having significantly greater inhibitory activity than their antipodes. See, e.g., U.S. Pat. No. 4,130,714.
Methods of obtaining enantiomerically pure forms of chiral hydantoins have been described previously. Conventional methods have involved resolution using the resolving agent brucine, or asymmetric synthesis using a method similar to a procedure described in Sarges, et al., J. Org. Chem., 47:4081 (1982). Such methods may, however, be unsatisfactory in achieving complete resolution of certain substituted spirofluorenehydantoins, such as 2,7-difluoro-4-methoxyspiro[9H-fluorene-9,4'-imidazolidine]-2',5'-dione. A method for synthesizing the pure R and S enantiomers of such spirofluorenehydantoins is described in commonly assigned U.S. Pat. No. 5,151,544 (DuPriest et al.). To the extent such compounds are susceptible to enantiomeric resolution or asymmetric synthesis, the more active enantiomer would typically be favored as a therapeutic agent, provided that its negative side-effects are not disproportionately greater than those of its antipode.
Thus, there is a need for compositions and methods which benefit the metabolically impaired patient and provide for more convenient dosing regimens for both poor and extensive metabolizers. The present invention teaches, inter alia, compositions and methods responsive to this need.